Glycogen Branching Enzyme 1

So we've talked a quite a bit about the GBE1 gene, where a missense mutation, that lead to the replacement of a tyrosine (tyr) amino acid with a serine (ser) amino acid (it's case specific), an amino acid with hydrophobic side chain, with a polar, uncharged side chain, gives a non-functional GBE protein. And this is the cause of all our problems in Andersen's Disease. So, let us understand a bit more about the Glycogen Branching Enzyme.

So you ate this. Ice-cream. You ate 3 tubs all by yourself for lunch at 12 noon and your blood glucose concentration rises as a result of the "meal". The blood also enters the beta cells of the Islets of Langerhans in the pancreas, and the glucose diffuses into the beta cell via vesicles. In the cell, the following biochemical reaction occurs:

Flashback to glycolysis chapter

G6P is subsequently oxidised to form ATP. The presence of ATP causes potassium ion channels to close for depolarization of the cell membrane to occur. Voltage-gated calcium channels open, for an influx of Ca2+ ions. This stimulates the release of insulin. Insulin will stimulate the action of several enzymes by binding to the insulin receptor for a cascade of reactions to occur.

An active form of glucose, UDP-glucose is formed through the formation of alpha-1-4 glycosidic bond, to give a linear glycogen chain. (Note UDP, Uridine triphosphate is similar to ATP, just more specific) This all occurs normally, even with a mutation in the GBE1 gene. It is in the second step of the production of branched glycogen where the issue begins.

The branching of glycogen requires a branching enzyme for the formation of an alpha-1,6 linkage between the core and the branch of around 6 residues. This will give rise to the formation of a branched glycogen. And as such, you can be a happy child and eat more ice-cream! (Please note, that pink-brown thing is supposed to be an ice-cream cone - I tried).

Thus, GBE is need since its involved in carbohydrate metabolism by it catalysing the transfer of a segment of a (1-->4)-alpha-D-glucan chain to a primary hydroxyl group in a similar glucan chain during glycogenesis. It acts on linear glycogen chains produced when UDP-glucose is synthesized through the formation of alpha-1-4 glycosidic bond. In humans, glycogen is the alpha glucan produced during glycogenesis.

Let's take note of something important here first:

Amylopectin

- Has both alpha-1-4 glycosidic bond & alpha-1,6 linkage

- Has less branching (branches are separated by 12-20 glucose units)

Glycogen

- Has both alpha-1-4 glycosidic bond & alpha-1,6 linkage

- Has MORE branching (interval of 8-10 glucose units)

- Thus, more glucose units present

 Alternate names of GBE:

- amylo-(1,4 to 1,6) transglucosidase

- branching enzyme 

- glycogen branching enzyme

- 1,4-alpha-glucan branching enzyme

Enzyme Commission (EC) Number: 2.4.1.18 (ExPASy)

Q04446 (UniPro/SwissProt)

Thus, without GBE / with a dysfunctional GBE, branched glycogen (polyglucosan bodies) may be created in a manner where it resembles amylopectin. Amylopectin-like polyglucosan bodies can be broken down by a type of amylase, however, the enzymes that are synthesized for glycogenolysis (the breaking down of glycogen) are just glycogen phosphorylase and the debranching enzyme. 

Insufficient research coupled with technological limitations has left its most of the molecular mechanism of GSD IV unknown and currently, incurable.

As such, the synthesised glycogen is unable to be degraded via proteolytic cleavage to give glucose. This leads to the:

- Accumulation of amylopectin-like polyglucosan bodies

- No glycogenolysis to get glucose

- No ice-cream for you

:(

Polyglucosan Bodies - Extra Reading

Oh dear... I can't believe I missed this important detail out of the blog when I was talking about abnormally structured glycogen or amylopectin-like deposits. 

Scientists studying Andersen's disease had given a name to such deposits or molecules, calling them polyglucosan bodies. 

Polyglucosan bodies is caused by a deficient Glycogen Branching Enzyme 1 gene (GBE1) that originally encodes for a 702 amino acids long, monomeric protein (2106 base pair mRNA) which makes a fully functional GBE. Since GBE is essential for making glycogen, a mutation to this gene would result in making abnormal glycogen molecules. 

This mutation may or may not cause Adult Polyglucosan Body Disease (APBD) as scientist are still unsure of the mechanisms of the disease itself. 

May or may not cause APBD? Sounds oddly familiar...
Psst Google Schrodinger's Cat if you don't understand this meme! It's quite interesting.... (so I say)

What exactly is a GBE1 mutation? 

It results in APBD which is a condition that affects the nervous system due to major loss (not entirely!) of the GBE1 gene function. At least 3 mutations in the GBE1 gene that causes APBD is known to scientist.

Located on the short (p) arm of the chromosome of chromosome 3 is GBE1 gene,
which is essential for proper branching of glycogen.

A version of the mutation is often seen in Ashkenazi Jewish ancestry is that the amino acid tyrosine (tyr) is replaced with the amino acid serine (ser) at the 329th amino acid. This leads to a deficient GBE1. So what's the big deal you ask? Well, it leads to polyglucosan due to lack of branching of glycogen which in turn leads to accumulation of polyglucosan bodies which are capable of causing cell damage. 

Scientist found out that neurons are more susceptible to the accumulation of polyglucosan bodies which leads to damaged neurons that can result in decreased sensation, vulnerability and other nervous systems disorders - most of which are symptoms of APBD.  

"Erm I thought your topic was on Andersen's disease?... I don't see the link here..."

As mentioned above, at least 3 mutations in the GBE1 gene leads to APBD but for Andersen's disease, a whopping amount of approximately 40 mutations in the GBE1 gene had been characterized by scientists. Single amino acids mutations also occur which results in the same accumulation of polyglucosan bodies. 

However, instead of targeting the neurons, Andersen's disease affects mostly the liver and muscle cells due to complete loss of enzyme activity instead of a partial loss like in APBD. Accumulation of glycogen leads to inability of your liver to function and coupled with the fact that your muscle cells are unable to break down "glycogen" for glucose (main source of energy), it leads to fatigue, enlarged liver, muscle weakness and most of the symptoms of Andersen's disease. 

Although scientist do know that these 2 diseases affect different part of the body, they are still unsure of the exact reason why this happen. 

I guess it must be frustrating to not have an end answer to their problems and questions. But science is always about a collective effort of finding out the truth! Hopefully with further research, it will be able to shed some light on the issue... 

Apologies for the extremely long post, but I hope we've given you some extra knowledge to take home and digest!

Some ice cream to make up for the long post!

Sources:

https://americanwicca.files.wordpress.com/2012/06/funny-pictures-schrodingers-cat-chemistry-cat.jpg?w=250

http://themedicalbiochemistrypage.org/andersendisease.php

http://ghr.nlm.nih.gov/gene/GBE1

http://ghr.nlm.nih.gov/dynamicImages/chromomap/GBE1.jpeg

http://www.slideshare.net/BenDecker/molecular-characterization-of-polyglucosan-body-cause-or-consequence-in-the-disease

http://biggapon.com.bd/wp-content/uploads/2014/12/andersens2.jpg

Dr Andersen

Meet Dr Dorothy Hansine Andersen. The American physician to first identify cystic fibrosis, which is a symptom of Glycogen Storage Disease Type IV. This correlation possibly led this disease to be named after her, and thus the name Andersen's Disease was born. There isn't much information about Dr Andersen, but one thing is for sure, she doesn't enjoy taking selfies.

Yup. That's all Google had.

But seriously speaking, having devoted her life to the study of fibrosis and studied the congenital defects of the heart, Dr Andersen managed to revolutionize techniques for surgeons and bring relief to many. Let celebrate Dr Andersen, awardee of the Distinguished Service Medal and Mead Johnson Award.

Treatments for Andersen's Disease

In the previous post, we discussed the possible symptoms of Andersen's Disease. We will now delve into the realm of possibilities with treatments for it.

As mentioned the disease is symptom-specific, thus, treatment for each patient varies. The constant between all patients though is the coordinated efforts of medical professionals, from pediatricians to physicians to cardiologists.

Treatment are better referred to as therapies as there is no cure for Andersen's disease. More funding for research of this disease may one day lead to the possible treatment of Andersen's disease by gene therapy, but until then, therapies directed at Andersen's disease aim to manage the disease.

Management of Andersen's Disease

• Treatment of manifestations
• Prevention of secondary complications
• Surveillance
• Genetic counselling

Treatment of manifestations

Supportive therapies may be directed toward managing the symptoms / effects brought by the disease, for example, cirrhosis, impaired liver function, neuromuscular disease or heart dysfunction. Medications and surgical interventions may be required if cardiomyopathy is involved and heart failure has to be circumvented. In the case of advanced stages of cirrhosis to the liver, a transplant may be required.

Prevention of secondary complications

Dietary measures are taken for patients to maintain normal glucose levels in the blood. This allows for an adequate nutritional intake to improve liver function and muscular strength. 

Surveillance
Assessment of liver, heart and the functions of other organs has tot be checked periodically.

Genetic counselling
Genetic counselling will benefit both the family and the affected individual to reduce the occurance of Andersen's disease in the bloodline.

These approaches are coupled together as the best approach for the long-term management of Andersen's Disease. It no doubt isn't the best, all-in-one solution to cure everything, but this is after all, the only viable solution available currently. The association for glycogen storage diseases (Type 0 to IX, where Type IV is Andersen's Disease) in the United Kingdom welcomes donation to sustain assistance to families affected by Glycogen Storage Disease. Do consider spreading word for the organization to gain more sponsorship and make a donation if possible.

Sources:

http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/394/viewFullReport
http://apbdrf.org/donations/?p=Anti-Sense_-_Recently_Approved_Gene_Therapy

Symptoms of Andersen's Disease

Yum yum. Yes, we know what you're thinking. It's time for a Christmas treat and ice-cream seem to be the perfect choice. All of us love ice-cream, as a child or as an adult - we love ice-cream (Or maybe its just me :D). However, ice-cream may not very well be the best choice for a snack for someone living with Andersen's Disease. (Not the compulsive disorder to eat ice-cream like me, but the other one, amylopectinosis / branching enzyme deficiency)

Previously, we talked about what Andersen's Disease is and its diagnosis. Let us now talk a little bit about the symptoms for the disease, since Andersen's disease is symptom-specific and treatment is unique for each patient based on the array of symptoms displayed. 

Andersen's disease affects the liver, muscles, heart, nervous system and more, thus, biopsies are taken for examination to look for abnormally structured glycogen or amylopectin-like deposits for diagnosis.

Having known these organs / systems are affected, we are able to better associate the symptoms with the disease itself. For example, accumulation of abnormal glycogen caused by the lack of a GBE in skeletal muscle may lead to muscle weakness and fatigue, because the glycogen then cannot be converted back to glucose to be used to produce energy for exercise.

Also, the presence of insoluble glycogen can induce foreign-body reactions to lead to cellular injury. The rapid injury to cells will lead to the replacement of tissue with scar tissue (fibrosis) and regenerative nodules. As such, a patient can develop cirrhosis, usually to the liver. This can lead to liver failure, that is irreversible.

There are many other symptoms found to be associated with Andersen's Disease. Some of which are:

• Muscle weakness & fatigue
• Cirrhosis
• Hypertension.
• Failure to grow & gain weight
• Hepatosplenomegaly (Enlargement of spleen)

There are many more symptoms that could be tell-tale signs of Andersen's Disease, but of course, like every other disease I have learnt, I always end up self diagnosing myself as an affected individual by this disease haha. 

Let's leave the diagnosing to the medical professionals for biopsies, counting of blood cells, testing liver functions and more.

Merry Christmas fellow bloggers!

Diagnosis of Andersen's Disease

Hello fellow classmates! Today we'll be talking about Andersen's Disease and how doctors diagnose Andersen's disease. 

Clinical evaluations are done either during infancy or childhood (and occasionally, adulthood). Family history is looked at to see if parents are carriers of the disease as it is a recessive disease (implying it requires 2 copies of the recessive allele for a person to be affected). 

                            

Biopsies are taken for examination which may show signs of abnormally structured glycogen or amylopectin-like deposits. Sample can be taken from muscle, liver tissue and even skin cells or blood cells for an indirect enzyme assay. 

Counting of blood cells, testing of liver functions and glucose level in blood may be done to aid in detection of symptoms that are associated with the disease. Such test can also be done prenatally by taking biopsy of the chorionic villi or via amniocentesis where the amniotic fluid is used. 

Diagrams showing how the prenatal test are administered. 

Sources:

http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/394/viewFullReport

http://www.babycenter.com/0_amniocentesis_327.bc#articlesection1

http://www.mamasonbedrest.com/wp-content/uploads/2010/02/amnioandCVS.jpg

What Exactly Causes Andersen's Disease?

Andersen's Disease is usally characterized by a lack of glycogen branching enzyme (GBE). As its name suggests, it exist to form multiple branch point during the formation of glycogen (which is what we want). Since we know that glucose is stored as glycogen which is essentially the branched form of glucose -plays flashback scene of MBC & Physiology lectures- , the lack of GBE leads to structurally abnormal glycogen!

So a glycogen with less branching point would look similar to amylopectin, which is the reason why Andersen's Disease is sometimes also known as Amylopectinosis.

So what's how do doctors diagnose a patient with Andersen's Disease? That's for you to find out in another blog post! 

Sources:

http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/394/viewFullReport

http://2012books.lardbucket.org/books/an-introduction-to-nutrition/section_08/83d76e165d784a9bc705cc259e416ed9.jpg